Journal of Inherited Metabolic Disease最新文献

{"title":"Vitamin-Responsive Disorders: From Molecular Basis to Clinical Presentation and Therapy","authors":"Cécile Acquaviva,&nbsp;Yann Nadjar,&nbsp;Manuel Schiff,&nbsp;Christine Vianey-Saban,&nbsp;Alain Fouilhoux,&nbsp;Jean-François Benoist","doi":"10.1002/jimd.70207","DOIUrl":"10.1002/jimd.70207","url":null,"abstract":"<p>Vitamin-dependent cofactors are essential for numerous metabolic reactions, and defects affecting their uptake, conversion, utilisation, or regeneration constitute a heterogeneous group of inherited metabolic disorders (IMDs). Although dietary vitamin intake is sufficient to sustain coenzyme synthesis in healthy individuals, it is insufficient in vitamin-responsive IMDs, where pharmacological supplementation can restore deficient metabolic fluxes or stabilise impaired enzymes. This review provides an integrated overview of the biochemical pathways that convert vitamins into their active coenzymes and documents all currently known hereditary disorders responsive to vitamin or coenzyme therapy, along with recommended doses. For each vitamin group (B₁, B₂, B₃, B₆, B₈, B₉, and B₁₂) and BH₄, we outline absorption, intracellular trafficking, coenzyme formation and turnover, major clinical phenotypes, diagnostic biomarkers, and vitamin therapeutic considerations, including dose ranges, formulation constraints, and safety issues. The expected therapeutic benefit is graded to assist with clinical decision-making. As many conditions are rare and have only recently been described, the evidence is sometimes limited; therefore, systematic reporting of individual responses, including vitamin forms and dosing, remains essential. Early recognition of vitamin-responsive IMDs is critical, as timely treatment can dramatically alter disease trajectories and, in some cases, fully reverse symptoms.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70207","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders","authors":"Giorgia Olivieri,&nbsp;Andrea Bordugo,&nbsp;Birute Burnyte,&nbsp;Alessandro Costetti,&nbsp;Maria-Luz Couce,&nbsp;Luisa Diogo,&nbsp;Francois Feillet,&nbsp;D. Sean Froese,&nbsp;Benedetta Greco,&nbsp;Jean-Louis Gueant,&nbsp;Luciana Hannibal,&nbsp;Friederike Hörster,&nbsp;Viktor Kožich,&nbsp;Giancarlo La Marca,&nbsp;Irini Manoli,&nbsp;Fanny Mochel,&nbsp;Lorenzo Orazi,&nbsp;Belén Pérez,&nbsp;Manuel Schiff,&nbsp;Bernd C. Schwahn,&nbsp;Ida Schwartz,&nbsp;Karolina M. Stepien,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Trine Tangeraas,&nbsp;Rolf H. Zetterström,&nbsp;Carlo Dionisi-Vici,&nbsp;Martina Huemer","doi":"10.1002/jimd.70177","DOIUrl":"10.1002/jimd.70177","url":null,"abstract":"<p>This guideline summarizes diagnostic and therapeutic approaches based on a systematic literature review and evidence evaluation using the GRADE methodology. Given the limited high-quality data, expert consensus was additionally obtained through a modified Delphi process. Remethylation disorders are rare inherited conditions that disrupt the methionine–homocysteine cycle and consecutively impair essential methylation dependent metabolic pathways. Remethylation disorders are caused by defects in the cobalamin or folate metabolism. The disorders typically result in elevated homocysteine and often low methionine; combined cobalamin-related defects also affect mitochondrial methylmalonic acid clearance. The cblC-<i>MMACHC</i> defect is the most common cobalamin-related remethylation disorder. Early-onset patients usually present with severe neurological and eye symptoms. Late-onset cases show variable symptoms (e.g., psychiatric, renal, thromboembolic events). Plasma total homocysteine, methionine, methylmalonic acid, serum vitamin B12 (and folates) should be assessed in suspected cases. Early detection through newborn screening is associated with improved clinical outcomes. Betaine as first-line therapy for methylenetetrahydrofolate reductase deficiency and parenteral hydroxocobalamin for cobalamin-related defects have reduced mortality and morbidity. Total homocysteine, methionine (and methylmalonic acid) should be kept as close to normal values as achievable. Emerging evidence suggests that early use of high-dose hydroxocobalamin (&gt; 0.35 mg/kg/day) may improve neurocognitive impairment and may ameliorate eye disease in severe cobalamin-related defects. A major limitation in current practice is the lack of availability of high concentration hydroxocobalamin formulations for parenteral administration.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Muscle MRI of the Lower Extremities Reveals Different Patterns of Involvement in Classic Infantile and Young Late-Onset Pompe Patients","authors":"Jan J. A. van den Dorpel,&nbsp;Mechteld E. Guldemond,&nbsp;Kevin R. Keene,&nbsp;Pieter A. van Doorn,&nbsp;Ans T. van der Ploeg,&nbsp;Johanna M. P. van den Hout,&nbsp;Hermien E. Kan,&nbsp;Nadine A. M. E. van der Beek","doi":"10.1002/jimd.70209","DOIUrl":"https://doi.org/10.1002/jimd.70209","url":null,"abstract":"<p>With increased survival due to enzyme replacement therapy, children with classic infantile Pompe disease tend to develop a clinical phenotype with pronounced distal muscle weakness, while late-onset patients typically exhibit proximal muscle weakness. This MRI study aimed to characterize lower limb muscle involvement in classic infantile and young late-onset Pompe patients compared to healthy controls, and examine its relationship with motor function. Quantitative MRI (3-point Dixon and multi-echo spin-echo at 3T) was used to assess fat fraction (FF) and water T2 (T2_water) in the leg muscles of eight classic infantile patients (6.6–15.0 years), 12 late-onset patients (6.8–27.3 years), and 13 healthy controls (6.5–26.9 years). Group comparisons were performed (Kruskal–Wallis, post hoc Dunn), and FF and T2_water values were combined to identify the most frequently affected muscles. MRI findings were correlated with Quick Motor Function Test (QMFT) scores for thigh involvement and Medical Research Council (MRC) scores for foot dorsiflexion strength. MRI showed fat replacement and T2_water abnormalities in numerous muscles in both patient groups. Fat replacement was generally mild (&lt; 20%) but reached 69% in some cases. T2_water values ranged from 21 to 37 ms. Classic infantile patients showed more frequent lower leg involvement (80% vs. 40%), while late-onset patients had predominant thigh involvement, particularly in the adductors. Extensive thigh involvement correlated with lower QMFT scores. Foot dorsiflexion weakness occurred only in classic infantile patients with tibialis anterior involvement. This data suggests a phenotype-specific pattern of muscle involvement and demonstrates the value of combining FF and T2_water via quantitative MRI for detection of muscle involvement in Pompe disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148100609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148083179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148074474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148065236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adults With Acid Sphingomyelinase Deficiency Have Sustained Improvements in Clinical Outcomes With up to 5 Years of Olipudase Alfa Enzyme Replacement Therapy: ASCEND Trial Final Results.","authors":"Melissa P Wasserstein, Carla E Hollak, Antonio Barbato, Renata C Gallagher, Roberto Giugliani, Norberto Bernardo Guelbert, Julia B Hennermann, Takayuki Ikezoe, Robin Lachmann, Olivier Lidove, Paulina Mabe, Eugen Mengel, Maurizio Scarpa, Ebubekir Senates, Michel Tchan, Beth L Thurberg, Jesus Villarrubia, Nicole M Armstrong, Shashi Bhushan, Yong Kim, Monica Kumar","doi":"10.1002/jimd.70192","DOIUrl":"10.1002/jimd.70192","url":null,"abstract":"<p><p>Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DL_CO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70192"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver Gene Therapy in Fabry Disease Mice With Low Doses of rAAV2/8 Expressing a Codon-Optimized hGLA cDNA Results in Long-Term Disease Correction.","authors":"Himanshi Saxena, Rossana Domenis, Giulia Romano, Jessica Biasizzo, Martina Ferro, Dania Ferino, Antonio Vicidomini, Alessandra Iaconcig, Giulia Bortolussi, Lorena Zentilin, Andrea Dardis, Andrés F Muro","doi":"10.1002/jimd.70188","DOIUrl":"10.1002/jimd.70188","url":null,"abstract":"<p><p>Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, which encodes for Alpha Galactosidase-A (α-Gal A). α-Gal A deficiency leads to glycosphingolipid accumulation, like globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), resulting in systemic symptoms and reduced lifespan. Current treatments such as enzyme replacement therapy (ERT) and chaperone therapy are noncurative and have limitations. Gene therapy is an interesting alternative approach that may overcome most of these limitations, and different approaches are currently being tested. Here, we developed a gene therapy approach using rAAV2/8 vectors, delivered intravenously, that target the liver to produce and secrete functional α-Gal A into circulation. This enzyme is then captured by organs expressing mannose-6-phosphate receptors, reducing glycosphingolipid accumulation in affected tissues. We generated a codon-optimized GLA cDNA with enhanced translatability that was expressed under a strong liver-specific promoter. In a dose escalation study in juvenile Gla knock-out (ko) mice, the lowest dose (3.0E11vg/kg) resulted in 85%-95% clearance of lyso-Gb3 in plasma and tissues, while doses of 3.0E12 vg/kg and higher showed 98%-100% clearance of the glycosphingolipid. All AAV doses were more effective than systemic α-Gal A administration (ERT). Long-term treatment showed normal levels of lyso-Gb3 in plasma and tissues, and corrected neuropathic involvement, as shown in the hot plate test. This study provides a proof-of-concept showing that the tested liver-specific gene therapy vector is capable of preventing disease progression in juvenile Fabry mice at relatively low doses and shows potential in treating both early- and late-onset FD in patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70188"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of Specific Urinary Oligosaccharide Biomarkers for Diagnosis and Treatment Monitoring of Alpha-Mannosidosis.","authors":"Dominik Dörfel, Benjamin Dreyer, Mona Lindschau, Antonio Barbato, Nadia Altavilla, Giancarlo la Marca, Lara Maleen Marten, Friederike Bürger, Mara Botti, Lina Verena Sevenich, Ronen Spiegel, Anke Schumann, Melanie Herrmann, Davor Fielitz, Nicole Muschol, René Santer, Simona Murko","doi":"10.1002/jimd.70208","DOIUrl":"10.1002/jimd.70208","url":null,"abstract":"<p><p>Alpha-mannosidosis (AM, OMIM# 248500), an ultra-rare lysosomal storage disorder (LSD), is caused by insufficient activity of alpha-mannosidase, an enzyme involved in degradation of N-glycan oligosaccharides. Hence, specific oligosaccharides accumulate in tissues, resulting in a progressive multi-organ disease. Therapeutic options exist but treatment outcome depends on early diagnosis. Thus, multiple methods have been developed for analysis of these oligosaccharides in urine that are qualitative or semi-quantitative, limiting their use for treatment monitoring. A rapid quantitative method without derivatization was developed for AM biomarkers GlcNAc(Man)₂, GlcNAc(Man)₃, and GlcNAc(Man)₄ in spot urine samples using ultra-performance liquid chromatography coupled to tandem-mass spectrometry. Urine samples of 208 controls, 20 AM patients, and 26 patients with other LSDs were analyzed. Method validation proved high recoveries (88%-108%) and precisions (standard deviation < 8%), low limits of quantification (0.12 μg GlcNAc(Man)₂/mL), and high sample stability. We observed a clear separation between controls and AM patients (0.0-9.0 vs 39.4-99.3 μmol GlcNAc(Man)₂/mmol creatinine, p < 0.0001). Furthermore, GlcNAc(Man)₂ concentration showed significant differences between untreated patients and those treated with enzyme replacement therapy (ERT; n = 13, p = 0.0006) or hematopoietic stem cell transplantation (HSCT; n = 3, p = 0.0143), and between both treatments (p = 0.0143). Thus, the developed method is well-suited for selective screening for AM and offers a simple way to monitor treatment efficacy.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70208"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Analysis of Dietary Patterns in Children With Phenylketonuria Phenotypes and Controls: Implications for Nutritional Status.","authors":"Dolores Garcia-Arenas, Aida Ormazabal, Paula Isern, Blanca Barrau-Martinez, Arnau Gonzalez-Rodriguez, Alba Tor-Roca, Rafael Llorach, Jaume Campistol-Plana, Mireia Urpi-Sarda","doi":"10.1002/jimd.70196","DOIUrl":"10.1002/jimd.70196","url":null,"abstract":"<p><p>Individuals with phenylketonuria (PKU), caused by different variants of the phenylalanine hydroxylase gene, need to restrict their intake of phenylalanine. This study evaluated dietary patterns and physical activity levels in children with different PKU phenotypes compared to healthy controls. Eighty-two children were recruited (22 classic PKU [cPKU], 21 BH₄-responsive PKU, 19 hyperphenylalaninemia, and 20 controls). Anthropometric data, dietary intake, biochemical markers, and physical activity were assessed. Classic PKU (cPKU) subjects exhibited higher carbohydrate and sugar intake than other PKU phenotypes and controls. Notably, 42% of carbohydrate and 17% of sugar intake was from special low-protein foods, and 20% of carbohydrate and 29% of sugar intake was from protein substitutes. Compared to controls, the cPKU group was less physically active and reported a higher frequency of sweet consumption. Ninety percent of PKU had good metabolic control and carbohydrate intake was significantly correlated with HOMA-IR; however, after adjusting for age, only a trend remained (p = 0.08). Participants in the PKU group following a low natural protein diet consumed more carbohydrate and sugars than those on a normal-protein diet. Multivariate regression analysis showed that the low natural protein diet group was significantly associated with higher levels of vitamin B₁₂, linoleic acid, α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, and with lower levels of total cholesterol and HDL-C compared to the normal-protein diet group. In conclusion, children with PKU, particularly those with classical PKU following low-protein diets, showed higher carbohydrate intake and distinct micronutrient and lipid profiles compared with healthy controls.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70196"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}